HIV and its rhesus macaque (RM) counterpart SIV share a pattern of infection and a constellation of immunologic and pathobiologic features such that the vast majority of susceptible (untreated) people or RM infected with these agents experience unremitting infection and progressive immune deficiency. In work funded by this grant, we pioneered analysis of the in vivo immunobiology of naive vs. memory (TN vs. TM) and central vs. effector memory (TCM vs. TEM) T cells in the RM model (including their homeostatic and functional regulation) and demonstrated the direct relevance of this physiology to SIV pathogenesis and immunity. In particular, we demonstrated that the mechanisms that maintain CD4* TCM homeostasis and regulate CD4'' TCM differentiation into CD4* TEM determine the development of immunodeficiency (AIDS) in SIV-infected RM. More recently, we have: 1) shown that IL-7 and IL-15 are critical regulators of CD4* TCM homeostasis in RM, 2) developed a TN-deficient RM model and used this model to show that CD4* TN are dispensable for both 004^ TCM stability and CD4* TEM production in SIV-infected RM, and 3) developed a method for long-term in vivo IL-15 blockade in RM (a rhesusized anti-IL-15 mAb) and used this method to show the importance of IL-15 in TEM homeostasis and that complete NK depletion (a second consequence of IL-15 blockade) has little impact on virologic control and disease progression in SIV-infected RM. In the extension of this work, we will use the CD4* and CD8* TN depletion models and in vivo manipulation of IL-15 and IL-7 to define the fundamental mechanisms underlying: 1) SIV persistence and replication set points (immune evasion vs. immune control), 2) deterioration of 004^ T cell-mediated and overall immunity leading to AIDS, and 3) the establishment and maintenance of SIV reservoirs and immune reconstitution following pharmacologic control of viral replication (using ART regimens capable of long-term suppression of SIV in RM to <30 RNA copies/mL of plasma and improved methods for monitoring residual viral RNA and DNA in tissues). Identification of these mechanisms will be a crucial step in the development of novel therapeutic approaches aimed at enhancing immune control of HIV replication, disconnecting HIV replication from disease progression, and/or augmenting imnnune recovery and reservoir clearance during anti-retroviral therapy.